WO2006064355A2 - Novel heterocyclic compounds useful for the treatment of inflammatory and allergic disorders - Google Patents

Novel heterocyclic compounds useful for the treatment of inflammatory and allergic disorders Download PDF

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Publication number
WO2006064355A2
WO2006064355A2 PCT/IB2005/003798 IB2005003798W WO2006064355A2 WO 2006064355 A2 WO2006064355 A2 WO 2006064355A2 IB 2005003798 W IB2005003798 W IB 2005003798W WO 2006064355 A2 WO2006064355 A2 WO 2006064355A2
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formula
substituted
unsubstituted
methoxy
furo
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PCT/IB2005/003798
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English (en)
French (fr)
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WO2006064355A3 (en
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Laxmikant Atmaram Gharat
Balasubramanian Gopalan
Neelima Khairatkar-Joshi
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Glenmark Pharmaceuticals S.A.
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Priority to CA2591438A priority Critical patent/CA2591438C/en
Priority to AU2005315319A priority patent/AU2005315319B2/en
Application filed by Glenmark Pharmaceuticals S.A. filed Critical Glenmark Pharmaceuticals S.A.
Priority to ES05826587T priority patent/ES2417491T3/es
Priority to CN2005800483152A priority patent/CN101124229B/zh
Priority to PL05826587T priority patent/PL1831227T3/pl
Priority to AP2007004031A priority patent/AP2334A/xx
Priority to SI200531753T priority patent/SI1831227T1/sl
Priority to JP2007546221A priority patent/JP5122974B2/ja
Priority to EP05826587.7A priority patent/EP1831227B1/en
Priority to EA200701268A priority patent/EA014956B1/ru
Priority to KR1020077014219A priority patent/KR101317119B1/ko
Priority to US11/721,912 priority patent/US7943634B2/en
Priority to NZ555809A priority patent/NZ555809A/en
Priority to BRPI0517211A priority patent/BRPI0517211B8/pt
Priority to MX2007007345A priority patent/MX2007007345A/es
Priority to DK05826587.7T priority patent/DK1831227T3/da
Publication of WO2006064355A2 publication Critical patent/WO2006064355A2/en
Publication of WO2006064355A3 publication Critical patent/WO2006064355A3/en
Priority to IL183827A priority patent/IL183827A/en
Priority to NO20073436A priority patent/NO20073436L/no
Priority to HK08101735.0A priority patent/HK1111147A1/xx
Priority to US13/087,826 priority patent/US8129401B2/en

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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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Definitions

  • the present invention relates to novel tricyclic phosphodiesterase type 4 (PDE4) inhibitors, and analogs, tautomers, enantiomers, diasteromers, regioisomers, stereoisomers, polymorphs, pharmaceutically acceptable salts, appropriate N-oxides, and pharmaceutically acceptable solvates thereof, pharmaceutical compositions containing them, and their use for treating conditions mediated by PDE-IV inhibition, such as asthma and chronic obstructive pulmonary disease (COPD).
  • PDE4 tricyclic phosphodiesterase type 4
  • Airway inflammation characterizes a number of severe lung diseases including asthma and chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • Events leading to airway obstruction include edema of airway walls, infiltration of inflammatory cells into the lung, production of various inflammatory mediators and increased mucous production.
  • the airways of asthmatic patients are infiltrated by inflammatory leukocytes, of which eosinophils are the most prominent component. The magnitude of asthmatic reactions is correlated with the number of eosinophils present in the lungs.
  • eosinophils The accumulation of eosinophils is found dramatically in the lungs of asthmatic patients although there are very few in the lungs of a normal individual. They are capable of lysing and activating cells and destroying tissues. When activated, they synthesize and release inflammatory cytokines such as IL-I, IL-3, and TNF- ⁇ and inflammatory mediators such as PAF, LTD4 and related oxygen species that can produce edema and broncho-constriction.
  • Tumor necrosis factor (TNF- ⁇ ) is also known to be involved in the pathogenesis of a number of autoimmune and inflammatory diseases. Consequently, manipulation of the cytokine signaling or biosynthetic pathways associated with these proteins may provide therapeutic benefit in those disease states.
  • TNF- ⁇ production in proinflammatory cells becomes attenuated by an elevation of intracellular cyclic adenosine 3',5'-monophosphate (cAMP).
  • cAMP cyclic adenosine 3',5'-monophosphate
  • PDE phosphodiesterase family of enzymes.
  • the phosphodiesterase enzymes play an integral role in cell signaling mechanisms by hydrolyzing cAMP and cGP to their inactive 5' forms. Inhibition of PDE enzymes thus results in an elevation of cAMP and/or cGP levels and alters intracellular responses to extra cellular signals by affecting the processes mediated by cyclic nucleotides.
  • PDEs The mammalian cyclic nucleotide phosphodiesterases (PDEs) are classified into ten families on the basis of their amino acid sequences and/or DNA sequence, substrate specificity and sensitivity to pharmacological agents [Soderling, S.H., Bayuga, SJ., and Beavo, J.A., Proc. Natl. Acad. ScL, USA, 96,7071-7076 (1999); Fujishige, K, Kotera, J., Michibata, H., Yuasa, K., Takebayashi, Si, Okamura, K. and Omori, K., J. Biol. Chem., 274, 18438-18445 (1999)]. Many cell types express more than one PDE and distribution of isoenzymes between the cells varies markedly. Therefore development of highly isoenzyme selective PDE inhibitors provides a unique opportunity for selective manipulation of various pathophysiological processes.
  • Phosphodiesterase type 4 is an enzyme which regulates activities in cells which lead to inflammation in the lungs.
  • PDE4 a cAMP-specific and Ca +2 - independent enzyme, is a key isozyme in the hydrolysis of cAMP in mast cells, basophils, eosinophils, monocytes and lymphocytes.
  • the association between cAMP elevation in inflammatory cells with airway smooth muscle relaxation and inhibition of mediator release has led to widespread interest in the design of PDE4 inhibitors [Trophy,T.J., Am. J. Respir. Crit. Care Med., 157, 351-370 (1998)].
  • TNF- ⁇ Excessive or unregulated TNF- ⁇ production has been implicated in mediating or exacerbating a number of undesirable physiological conditions such as osteoarthritis and other arthritic conditions, septic shock, endotoxic shock, respiratory distress syndrome and bone resorption diseases. Since TNF- ⁇ also participates in the onset and progress of autoimmune diseases, PDE4 inhibitors may find utility as therapeutic agents for rheumatoid arthritis, multiple sclerosis and Crohn's disease. [Nature Medicine, I, 21 1- 214 (1995) and ibid., 244-248].
  • PDE4 family has grown to include four subtypes - PDE4A to PDE4D, each encoded by a distinct gene (British Journal of Pharmacology; 1999; v.128; p.1393-1398).
  • PDE-4 There exist two binding sites on mammalian PDE-4 at which inhibitor molecules may bind. Also PDE-4 exists in two distinct forms which represent different conformations. They are designated as High affinity Rolipram binding site PDE-4H and Low affinity Rolipram binding site PDE-4L [Jacobitz, S., McLaughlin, M.M., Livi, G.P., Burman, M., Trophy, T. J., MoI. Pharmaco., 50, 891-899 (1996)]. It was shown that certain side effects (vomiting and gastric acid secretion) are associated with inhibition of PDE-4H whereas some beneficial actions are associated with PDE-4L inhibition.
  • the present invention relates to new heterocyclic compounds which inhibit PDE-4 having the formula below:
  • Ar is substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl ring, or substituted or unsubstituted heteroarylalkyl;
  • L is O, S or NR a , where R a is as defined above; n is an integer from O to 2; p is an integer from O to 8;
  • Y is-C(O)NR 4 -, -NR 4 SO 2 -, -SO 2 NR 4 - or -NR 4 C(O)-;
  • R 4 is hydrogen, substituted or unsubstituted alkyl, hydroxyl, -0R a (wherein R a is defined above), substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic ring,substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl ring or substituted or unsubstituted heteroarylalkyl, or an analog, tautomer, regioisomer, stereoisomer, enantiomer, diastereomer, polymorph, pharmaceutically acceptable salt, N-oxide, or pharmaceutically acceptable solvate thereof.
  • Ar is optionally substituted phenyl, optionally substituted pyridyl or optionally substituted pyridyl-N-oxide in which the one or more optional substituents may be same or different and are independently hydrogen, hydroxyl, halogen, cyano, nitro, carboxyl, trifluoroalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted amino or mono or di substituted or unsubstituted alkylamino.
  • T and U are C
  • V is NR a
  • T, U, V, or W is NR a , where R a is hydrogen. More preferably, T and W are not NR a .
  • T, U, V, or W is NR a , where R a is methyl. More preferably, T and W are not NR a .
  • T, U, V, or W is NR a , where R a is - COO-t-Butyl (tert-butyloxy carbonyl). More preferably, T and W are not NR a .
  • T, U, V, or W is NR a , where R a is - COOEt. More preferably, T and W are not NR a .
  • the compound has the formula wherein
  • U and V are each independently C, N, or NR a (where R a is as defined above), with the proviso that at least one of U and V is N or NR a ; both dotted lines represent double bonds or both dotted lines are absent; each occurrence of R 1 , R 2 and R 3 may be same or different and are as defined above; and
  • Ar, R 4 , n, and p are as defined above, or a pharmaceutically acceptable salt thereof.
  • R 1 is substituted or unsubstituted alkyl (preferably CH 3 or CHF 2 ), and R 4 is hydrogen.
  • R a can be, for example, -COO-R a , where R a is a substituted or unsubstituted alkyl and preferably an unsubstituted Ci-C 6 alkyl.
  • Ar is an optionally substituted phenyl, optionally substituted pyridyl or optionally substituted pyridyl-N-oxide in which the one or more optional substituents may be same or different and are independently hydrogen, hydroxyl, halogen, cyano, nitro, carboxyl, trifluoroalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted amino or mono or di substituted or unsubstituted alkylamino.
  • Ar is an optionally substituted phenyl, optionally substituted pyridyl or optionally substituted pyridyl-N-oxide in which the one or more optional substituents may be same or different and are independently hydrogen, hydroxyl,
  • the compound has the formula wherein either (i) U is N, V is N or C, and both dotted lines represent double bonds, or (ii) U is NR a (where R a is as defined above), V is C, and both dotted lines are absent; each occurrence of R 1 , R 2 and R 3 may be same or different and are as defined above; and
  • Ar, n, and p are as defined above, or a pharmaceutically acceptable salt thereof.
  • n and p are 0, and R 1 is substituted or unsubstituted alkyl.
  • R a can be, for example, -COO-R a , where R a is a substituted or unsubstituted alkyl and preferably an unsubstituted Ci-C 6 alkyl.
  • Ar is an optionally substituted phenyl, optionally substituted pyridyl or optionally substituted pyridyl-N-oxide in which the one or more optional substituents may be same or different and are independently hydrogen, hydroxyl, halogen, cyano, nitro, carboxyl, trifluoroalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted amino or mono or di substituted or unsubstituted alkylamino.
  • Ar is an optionally substituted phenyl, optionally substituted pyridyl or optionally substituted pyridyl-N-oxide in which the one or more optional substituents may be same or different and are independently hydrogen, hydroxyl,
  • the compounds of formula (1) can contain one or more asymmetrically substituted carbon atoms.
  • the presence of one or more of these asymmetric centers in the compounds of formula (1 ) can give rise to stereoisomers and in each case the invention is to be understood to extend to all such stereoisomers, including enantiomers and diastereomers and their mixtures, including racemic mixtures.
  • the invention may also contain E and Z geometrical isomers wherever possible in the compounds of formula (1) which includes the single isomer or mixture of both the isomers
  • Another embodiment of the invention is a pharmaceutical composition containing one or more of the heterocyclic compounds of the present invention and a pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • a pharmaceutically acceptable excipient such as a pharmaceutically acceptable carrier or diluent.
  • the pharmaceutical composition may be, for example, a unit dosage form (such as a tablet or capsule).
  • the compounds of formula (1) down regulate or inhibit the production of TNF- ⁇ as they are PDE4 inhibitors and therefore are useful in the treatment of allergic and inflammatory diseases including asthma, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjuctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, septic shock, diabetes, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock and adult respiratory distress syndrome.
  • the compounds of the present invention are particularly useful for the treatment of asthma and chronic obstructive pulmonary disease (COPD).
  • Yet another embodiment of the invention is a method of treating an inflammatory disease, disorder or condition characterized by or associated with an undesirable inflammatory immune response, or a disease or condition induced by or associated with an excessive secretion of TNF- ⁇ and PDE-4 in a subject in need thereof by administering to the subject a therapeutically effective amount of a PDE-4 inhibitor or a pharmaceutical composition of the present invention.
  • Yet another embodiment of the invention is a method of treating an inflammatory condition or an immune disorder in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound according to formula (I) or a pharmaceutical composition of the present invention.
  • Inflammatory conditions and immune disorders which can be treated with the PDE-4 inhibitors of the present invention include, but are not limited to, asthma, bronchial asthma, chronic obstructive pulmonary disease, allergic rhinitis, eosinophilic granuloma, nephritis, rheumatoid arthritis, cystic fibrosis, chronic bronchitis, multiple sclerosis, Crohn's disease, psoraisis, uticaria, adult vernal cojunctivitis, respiratory distress syndrome, rhematoid spondylitis, osteoarthritis, gouty arthritis, uveits, allergic conjunctivitis, inflammatory bowel conditions, ulcerative coalitis, eczem
  • inflammatory conditions and immune disorders selected from inflammatory conditions and immune disorders of the lungs, joints, eyes, bowels, skin or heart.
  • inflammatory conditions chosen from the group consisting of asthma and chronic obstructive pulmonary disease.
  • Yet another embodiment of the invention is a method for abating inflammation in an affected organ or tissue by delivering to the organ or tissue a therapeutically effective amount of a PDE-4 inhibitor or a pharmaceutical composition of the present invention.
  • Yet another embodiment of the invention is a method of treating a disease of the central nervous system in a subject in need thereof by administering to the subject a therapeutically effective amount of a PDE-4 inhibitor or a pharmaceutical composition of the present invention.
  • Preferred diseases of the central nervous system include, but are not limited to, depression, amnesia, dementia, Alzheimers disease, cardiac failure, shock and cerebrovascular disease.
  • Yet another embodiment of the invention is a method of treating insulin resistant diabetes in a subject in need thereof by administering to the subject a therapeutically effective amount of a PDE-4 inhibitor or a pharmaceutical composition of the present invention.
  • the present invention also relates to processes for the preparation of the novel heterocyclic compounds of formula (1) as defined above.
  • alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1 -methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl).
  • alkenyl refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be a straight or branched chain having 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l-propenyl, 1-butenyl, and 2-butenyl.
  • alkynyl refers to a straight or branched chain hydrocarbyl radical having at least one carbon-carbon triple bond, and having in the range of 2 up to about 12 carbon atoms (with radicals having in the range of about 2 up to 10 carbon atoms presently being preferred), e.g., ethynyl, propynyl, and butynyl.
  • alkoxy refers to an alkyl group as defined above attached via an oxygen linkage to the rest of the molecule.
  • Non-limiting examples of such groups include -OCH 3 , and -OC 2 H 5 .
  • alkylcarbonyl refers to an alkyl group as defined above attached via a carbonyl linkage to the rest of the molecule.
  • Non-limiting examples of such groups include -C(O)CH 3 , and -C(O)C 2 H 5 .
  • alkoxycarbonyl refers to an alkoxy group as defined above attached via a carbonyl linkage to the rest of the molecule.
  • Non-limiting examples of such groups include -C(O)-OCH 3 , and -C(O)-OC 2 H 5 .
  • alkylcarbonyloxy refers to an alkylcarbonyl group as defined above attached via an oxygen linkage to the rest of the molecule.
  • Non-limiting examples of such groups include -0-C(O)CH 3 , and - 0-C(O)C 2 H 5 .
  • alkylamino refers to an alkyl group as defined above attached via an amino linkage to the rest of the molecule.
  • Non-limiting examples of such groups include -NH 2 CH 3 , -NH(CH 3 ) 2 , and -N(CH 3 ) 3 .
  • cycloalkyl refers to a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • multicyclic cycloalkyl groups include perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or sprirobicyclic groups, e.g., sprio (4,4) non-2-yl.
  • cycloalkylalkyl refers to a cyclic ring-containing radical containing in the range of 3 up to about 8 carbon atoms directly attached to an alkyl group which are then attached to the main structure at any carbon from the alkyl group that results in the creation of a stable structure.
  • Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.
  • cycloalkenyl refers to a cyclic ring-containing radical containing in the range of 3 up to about 8 carbon atoms with at least one carbon-carbon double bond such as cyclopropenyl, cyclobutenyl, and cyclopentenyl.
  • cycloalkenylalkyl refers to a cyclic ring-containing radical containing in the range of about 3 up to 8 carbon atoms with at least one carbon- carbon double bond directly attached to an alkyl group which is then attached to the main structure at any carbon from the alkyl group that results in the creation of a stable structure.
  • Non-limiting examples of such groups include cyclopropenylmethyl, cyclobutenylethyl, and cyclopentenylethyl.
  • aryl refers to an aromatic radical having in the range of 6 up to 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.
  • arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH 2 CeHs, and -C 2 H 5 CeHs.
  • heterocyclic ring refers to a stable 3- to 15 membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated (i.e., heteroaromatic).
  • heterocyclic ring radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, imidazolyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolidinyl
  • heteroaryl refers to an aromatic heterocyclic ring radical.
  • the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • heteroarylalkyl refers to heteroaryl ring radical as defined above directly bonded to an alkyl group.
  • the heteroarylalkyl radical may be attached to the main structure at any carbon atom from alkyl group that results in the creation of a stable structure.
  • heterocyclyl refers to a heterocylic ring radical as defined above.
  • the heterocylcyl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • heterocyclylalkyl refers to a heterocylic ring radical as defined above directly bonded to an alkyl group.
  • the heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • cyclic ring refers to a cyclic ring containing 3-10 carbon atoms.
  • protecting group refers to a substituent that is employed to block or protect a particular functionality while other functional groups on the compound may remain reactive.
  • an "amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include, but are not limited to, acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9- fluorenylmethylenoxycarbonyl (Fmoc).
  • a "hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality.
  • Suitable hydroxy-protecting groups include, but are not limited to, acetyl, benzyl, tetrahydropyranyl and silyl.
  • a "carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality.
  • Suitable carboxy-protecting groups include, but are not limited to, -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p- toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, and nitroethyl.
  • protecting groups and their use see, T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.
  • halogen refers to a radical of fluorine, chlorine, bromine or iodine.
  • the substituents in the aforementioned "substituted” groups cannot be further substituted.
  • the substituent on “substituted alkyl” is "substituted aryl”
  • the substituent on “substituted aryl” cannot be “substituted alkenyl”.
  • Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases (such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn), salts of organic bases (such as N,N'-diacetylethylenediamine, glucamine, triethylamine, choline, hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamine, thiamine, and the like), salts of chiral bases (such as alkylphenylamine, glycinol, phenyl glycinol and the like), salts of natural amino acids (such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, ornithine, lysine, arginine, serine, and the like), salts of non-
  • salts include acid addition salts (where appropriate) such as sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, fumarates, succinates, palmoates, methanesulphonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like.
  • salts include, but are not limited to, quaternary ammonium salts of the compounds of the present invention with alkyl halides or alkyl sulphates (such as Mel and (Me) 2 SO 4 ).
  • Pharmaceutically acceptable solvates may be hydrates or comprise other solvents of crystallization such as alcohols.
  • solvates include hydrates and other solvents of crystallization (such as alcohols).
  • the compounds of the present invention may form solvates with low molecular weight solvents by methods known in the art.
  • treating or “treatment” of a state, disorder or condition includes:
  • the benefit to a subject to be treated is either statistically significant or at least perceptible to the subject or to the physician.
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a state, disorder or condition, is sufficient to effect such treatment.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.
  • Delivery a therapeutically effective amount of an active ingredient to a particular location within a host means causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished , e.g., by local or by systemic administration of the active ingredient to the host.
  • the classic symptoms of acute inflammation are redness, elevated temperature, swelling, and pain in the affected area, and loss of function of the affected organ.
  • Symptoms and signs of inflammation associated with specific conditions include:
  • insulin-dependent diabetes mellitus- insulitis this condition can lead to a variety of complications with an inflammatory component, including: retinopathy, neuropathy, nephropathy; coronary artery disease, peripheral vascular disease, and cerebrovascular disease;
  • inflammatory skin disorders such as, eczema, other dermatites (e.g., atopic, contact), psoriasis, burns induced by UV radiation (sun rays and similar UV sources)- erythema, pain, scaling, swelling, tenderness;
  • inflammatory bowel disease such as Crohn's disease, ulcerative colitis- pain, diarrhea, constipation, rectal bleeding, fever, arthritis;
  • lung injury such as that which occurs in adult respiratory distress syndrome- shortness of breath, hyperventilation, decreased oxygenation, pulmonary infiltrates;
  • inflammation accompanying infection such as sepsis, septic shock, toxic shock syndrome- fever, respiratory failure, tachycardia, hypotension, leukocytosis;
  • nephritis e.g., glomerulonephritis
  • oliguria e.g., urinalysis
  • Type II diabetes- end organ complications including cardiovascular, ocular, renal, and peripheral vascular disease ,lung fibrosis- hyperventilation, shortness of breath, decreased oxygenation;
  • vascular disease such as atherosclerosis and restenosis- pain, loss of sensation, diminished pulses, loss of function and alloimmunity leading to transplant rejection- pain, tenderness, fever.
  • Subclinical symptoms include without limitation diagnostic markers for inflammation the appearance of which may precede the manifestation of clinical symptoms.
  • One class of subclinical symptoms is immunological symptoms, such as the invasion or accumulation in an organ or tissue of proinflammatory lymphoid cells or the presence locally or peripherally of activated pro-inflammatory lymphoid cells recognizing a pathogen or an antigen specific to the organ or tissue. Activation of lymphoid cells can be measured by techniques known in the art.
  • the compounds of the invention are effective over a wide dosage range.
  • dosages from about 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, per day may be used.
  • a most preferable dosage is about 0.5 mg to about 250 mg per day.
  • the exact dosage will depend upon the mode of administration, on the therapy desired, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
  • the compounds of the present invention are dispensed in a unit dosage form comprising from about 0.05 to about 1000 mg of active ingredient together with a pharmaceutically acceptable carrier.
  • dosage forms suitable for oral, nasal, pulmonal or transdermal administration comprise from about 0.05 mg to about 1000 mg, preferably from about 0.5 mg to about 250 mg of the compounds admixed with a pharmaceutically acceptable carrier or diluent.
  • the compounds of formula (I) may be prepared by the following processes.
  • the symbols Ar, T, U, V, W, X, Y, R 1 , R 2 , and R 3 when used in the formulae below are to be understood to represent those groups described above in relation to formula (1) unless otherwise indicated.
  • an appropriately substituted aromatic compound (10) can be reacted with 2-chloroacetoacetate, for example, in the presence of a base (such as sodium hydroxide and the like), to obtain the intermediate of the formula (1 1) which can then be cyclised, for example, under acidic conditions (such as polyphosphoric acid (PPA) or methanesulfonic acid and the like), to obtain the intermediate of the formula (12).
  • the intermediate of the formula (12) can then be formylated, for example, with dichloromethyl methyl ether in the presence of tin chloride, to the intermediate of the formula (13).
  • the intermediate of the formula (13) can then be oxidized to the carboxylic acid intermediate of the formula (14), for example with oxidizing agents such as sodium chlorite or potassium permanganate.
  • the intermediate of the formula (14) can then be esterified to give the intermediate of the formula (15).
  • the intermediate of formula (15) can then be converted to the intermediate of the formula (17) via the intermediate of formula (16) using radical bromination followed by oxidation with, for example, alkaline DMSO.
  • the intermediate (17) thus formed can then be reacted with hydrazine hydrate to obtain the intermediate of the formula (18) which can be aromatized using known methods in the art such as phosphorus oxychloride to give the intermediate of formula (19).
  • the intermediate of formula (19) is converted to the intermediate of formula (21).
  • the final compounds (1) can be prepared by reacting the acid halide or the mixed anhydride or active ester of the intermediate of the formula (21) with an appropriate amine of the formula ArNHR 4 , for example, using standard basic conditions such as those known in the literature (e.g., in the presence of sodium hydride in DMF or diisopropylethyamine in THF).
  • the intermediate (17a) can be reacted with hydrazine hydrate to obtain the intermediate of formula (18a).
  • Intermediate (18a) can then be reacted with a compound of formula R a -G (wherein G is a leaving group) to yield the intermediate of formula (19a).
  • the intermediate of formula (19a) can be hydrolysed to give the intermediate of formula (20a).
  • the final compound of formula (1) can be prepared by reacting the acid halide or the mixed anhydride or active ester of the intermediate of the formula (20a) with an appropriate amine of the formula ArNHR 4 , for example, using standard basic conditions such as those known in the literature (e.g., in the presence of sodium hydride in DMF or diisopropylethyamine in THF).
  • the intermediate (17a) can be reacted with a intermediate of general formula NH 2 -NHR a to obtain the intermediate of formula (19a).
  • the intermediate of formula (19a) can then be hydrolyzed to give the intermediate of formula (20a).
  • the final compounds of formula (1) can be prepared by reacting the acid halide or the mixed anhydride or active ester of the intermediate of the formula (20a) with an appropriate amine of the formula ArNHR 4 , for example, using standard basic conditions such as those known in the literature (e.g., in the presence of sodium hydride in DMF or diisopropylethyamine in THF).
  • an appropriately substituted aromatic aldehyde (22) can be converted to the intermediate of formula (23), such as by reacting it with ethylbromoacetate in the presence of a base such as potassium carbonate and the like.
  • the formyl group of the intermediate of formula (23) can then be converted to the cyano group using a standard aldehyde to oxime to nitrile process via an intermediate of formula (24) to get the intermediate of formula (25).
  • Cyclisation for example, in the presence of an appropriate amide such as formamide or acetamide, can give the intermediate of formula (26).
  • the intermediate of formula (26) can be converted to the intermediate of formula (28).
  • intermediate of formula (26) treatment of the intermediate of formula (26) with phosphorus oxychloride to give the intermediate of formula (27) followed by dechlorination, such as under hydrogenation in the presence of palladium on carbon, can give the intermediate of formula (28).
  • Intermediate (28) can then be brominated, for example, using bromine in acetic acid, to give an intermediate of formula (29) followed by displacement of the bromine with cyanide, for example, using copper cyanide in DMF, to give the intermediate of formula (30).
  • Hydrolysis such as with sulfuric acid, yields the carboxylic acid intermediate of formula (31).
  • the final compounds of formula (1) are prepared by reacting the acid halide or the mixed anhydride or active ester of the intermediate of formula (31) with an appropriate amine of the formula ArNHR 4 , for example, using standard basic conditions such as those known in the literature (e.g., in the presence of sodium hydride in DMF or diisopropylethyamine in THF and the like).
  • the intermediate (34) can be obtained by reacting the compound of formula (32) (wherein Zi is Br or I and Z 2 is F or Cl) with the compound of formula (33) (wherein FG is alkyl, formyl, acetyl, cyano or ester), for example, under appropriate basic conditions such as potassium carbonate in DMF.
  • the intermediate of formula (34) can then be cyclised to the intermediate of formula (35), for example, using catalytic palladium or nickel salts.
  • the functional group (FG) in the intermediate of formula (35) can then be converted to the carboxylic acid (if FG is alkyl, formyl or acetyl then it can be oxidized or if FG is cyano or ester then it can be hydrolysed to the carboxylic acid) to obtain the intermediate of formula (36).
  • the final compounds of formula (1) can then be prepared by reacting the acid halide or the mixed anhydride or active ester of the intermediate of formula (36) with an appropriate amine of the formula ArNHR 4 , for example, using standard basic conditions such as those known in the literature (e.g., in the presence of sodium hydride in DMF or diisopropylethyamine in THF and the like).
  • General Scheme IV
  • the intermediate of formula (39) can synthesized by reacting the appropriately substituted or unsubstituted intermediate of formula (37) (wherein Z is a halogen) with an appropriately substituted aryl intermediate of formula (38), for example, under appropriate basic conditions such as potassium carbonate in DMF.
  • Intermediate (39) can be cyclized, for example, under standard acidic conditions such as with polyphosphoric acid or methane sulfonic acid, to give the intermediate of formula (40) which further can be formylated, for example, using standard literature methods such as dichlormethylmethyl ether in the presence of a lewis acid (such as tin chloride), to give the intermediate of formula (41).
  • the formyl group of the intermediate of formula (41) can then be oxidized to a carboxylic acid to obtain the intermediate of formula (42).
  • the final compounds of formula (1) can then be prepared by reacting the acid halide or the mixed anhydride or active ester of the intermediate of formula (42) with an appropriate amine of the formula ArNHR 4 , for example, using standard basic conditions such as those known in the literature (e.g., in the presence of sodium hydride in DMF or diisopropylethyamine in THF and the like).
  • the intermediate (43) can be synthesized by reacting the intermediate of formula (38) and propargyl bromide, for example, in the presence of a suitable base such as potassium carbonate.
  • the intermediate of formula (43) can be subjected to cyclisation, such as in the presence of cesium fluoride, to afford the intermediate (44).
  • Intermediate (45) can be formed by formylation of the intermediate (44), such as with dichloromethylmethyl ether in the presence of tin (IV) chloride.
  • Intermediate (45) can be oxidized, such as with an oxidizing agent (e.g., sodium chlorite, potassium permanganate, or hydrogen peroxide), followed by esterification to yield the intermediate of formula (46), wherein R 7 is unsubstituted or substituted alkyl, unsubstituted or substituted aryl, or substituted or substituted arylalkyl.
  • the intermediate of formula (48) can be further obtained by bromination of the interemediate of formula (46), such as with NBS, to yield the intermediate of formula (47), followed by oxidative debromination, such as with dimethylsufoxide in the presence of a base such as sodium carbonate.
  • the intermediate (48) can be converted to the intermediate of formula (49), such as with malonic acid in the presence of a base such as piperidine.
  • the azido intermediate of formula (50) can then be obtained by treatment of intermediate (49) with, for example, ethyl chloroformate followed by sodium azide.
  • the azido intermediate (50) can be cyclized, for example at a temperature of 180 0 C or more, to provide the intermediate of formula (51).
  • Intermediate (51) can be converted, for example, by treatment with phosphorus oxychloride, to form the intermediate of formula (52). Reductive dechlorination of the intermediate (52), for example, with Pd/C or Raney nickel, affords the intermediate (53).
  • the final compounds of formula (1) can be prepared by reacting the acid halide or the mixed anhydride or active ester of the intermediate of formula (54) with an appropriate amine of the formula ArNHR 4 , for example, using standard basic conditions such as those known in the literature (e.g., in the presence of sodium hydride in DMF or diisopropylethyamine in THF and the like).
  • the desired compounds of formula (1) wherein Y is -CONR 4 , V is -NR a , T, U, and W are C, the dotted lines [ — ] between T and U and between V and W in the ring are absent, the remaining dotted line represents a bond, p 0 or 1, and Ar, X, R 1 , R 2 , R 3 , R a and n are as described in the general description, can be synthesized as described in the general scheme VI.
  • the intermediate (55) can be synthesized by reacting the intermediate of formula (38) with 4-chloroethylacetoacetate, for example, in the presence of a suitable base such as potassium carbonate.
  • Intermediate (55) can be cyclized, such as in the presence of polyphosphoric acid or sulfuric acid, to afford the intermediate of formula (56).
  • This intermediate can be converted to the amide intermediate of formula (57), for example with ammonia (such as in methanol).
  • Reduction of amide intermediate (57) using reducing agents such as borane in THF or lithium aluminium hydride provides the amine intermediate of formula (58).
  • the intermediate of formula (60) can be obtained by treating amine intermediate (58), for example, with ethyl chloroformate, to form the intermediate of formula (59) followed by cyclization, for example, in the presence of formaldehyde and an acid catalyst such as p-toluenesulfonic acid.
  • Intermediate (60) can be formylated, for example using standard conditions such as dichloromethylmethyl ether in the presence of tin (IV) chloride, to obtain the intermediate of formula (61).
  • Intermediate (61) ca nbe oxidized, for example with an oxidizing agent such as sodium chlorite, potassium permanganate or hydrogen peroxide, to form the intermediate of formula (62).
  • the ethyl carbamate portion of the intermediate (62) can be converted to t-butyl carbamate, for example, by basic hydrolysis followed by treatment with, for example, BOC-anhydride to obtain the intermediate of formula (63).
  • the final compounds of formula (1) can be prepared by reacting the acid halide or the mixed anhydride or active ester of the intermediate of the formula (63) with an appropriate amine of the formula ArNHR 4 , for example, using standard basic conditions such as those known in the literature (e.g., in the presence of sodium hydride in DMF or diisopropylethylamine in THF and the like).
  • the intermediate (58) can be synthesized as described in general scheme VIA.
  • the nitrile intermediate (69) can be further reduced to the amino intermediate of formula (70) with a reducing agent, such as lithium aluminum hydride, borane, or Pd/C hydrogenation.
  • a reducing agent such as lithium aluminum hydride, borane, or Pd/C hydrogenation.
  • the tricyclic intermediate of formula (72) can be obtained by treating the amine intermediate of formula (70) with, for example, ethyl chloroformate, to form the intermediate of formula (71) followed by cyclization, for example, in the presence of formaldehyde and an acid catalyst such as p-toluenesulfonic acid.
  • Intermediate (72) can be formylated, for example using standard conditions such as dichloromethylmethyl ether in the presence of tin (IV) chloride to obtain the intermediate of formula (73).
  • Intermediate (73) can be oxidized with an oxidizing agent, such as sodium chlorite, potassium permanganate, or hydrogen peroxide, to form the acid intermediate of formula (74).
  • an oxidizing agent such as sodium chlorite, potassium permanganate, or hydrogen peroxide
  • the ethyl carbamate portion of intermediate (74) can be converted to t-butyl carbamate by, for example, basic hydrolysis followed by treatment with BOC-anhydride to obtain the intermediate of formula (75).
  • the final compounds of formula (1) can be prepared by reacting the acid halide or the mixed anhydride or active ester of the intermediate of formula (75) with an appropriate amine of the formula ArNHR 4 , for example, using standard basic conditions such as those known in the literature (e.g., in the presence of sodium hydride in DMF or diisopropylethyamine in THF and the like).
  • the intermediate of formula (76) when reacted with the intermediate of formula (77) can provide the intermediate of formula (78), which on acid catalyzed cyclization can provide the intermediate of formula (79).
  • Reacting intermediate (79) with an intermediate of the formula R a -G wherein G is a leaving group (for example R a -G can be an alkyl halide (e.g., iodomethane, ethyl bromide and the like)) in the presence of a base (such as sodium hydride or potassium carbonate) forms the intermediate of formula (80).
  • Hydrolysis of intermediate (80) for example, in the presence of a base, such as sodium hydroxide, provides the acid intermediate of formula (81).
  • the final compounds of formula (1) can be prepared by reacting the acid halide or the mixed anhydride or active ester of intermediate (81) with an appropriate amine of the formula ArNHR 4 , for example, using standard basic conditions such as those known in the literature (e.g., in the presence of sodium hydride in DMF or diisopropylethyamine in THF and the like).
  • the desired compounds of formula (1) wherein Y is -CONR 4 , U is -NR a , S(O) m , or O, T, V, and W are C, the dotted lines [ — ] between T and U and between V and W in the ring are absent, the remaining dotted line represents a double bond, p 0, X is NR b , and Ar , R 1 , R 2 , R 3 , R b and n are as described in the general description, can be synthesized as described in the general scheme IX.
  • the intermediate of formula (82) can be obtained by reduction of the intermediate of formula (77), wherein R 7 is unsubstituted or substituted alkyl, unsubstituted or substituted aryl or substituted or substituted arylalkyl.
  • R b -G can be an alkyl halide (e.g., iodomethane, ethyl bromide and the like)) in the presence of a base (such as sodium hydride or potassium carbonate) to provide the intermediate of formula (85).
  • a base such as sodium hydride or potassium carbonate
  • Hydrolysis of intermediate (85) for example, in the presence of a base such as sodium hydroxide, provides the acid intermediate of formula (86).
  • the final compounds of formula (1) can be prepared by reacting the acid halide or the mixed anhydride or active ester of intermediate (86) with an appropriate amine of the formula ArNHR 4 , for example, using standard basic conditions such as those known in the literature (e.g., in the presence of sodium hydride in DMF or diisopropylethyamine in THF and the like).
  • the intermediate of formula (87) wherein T, U ,V, W, R 1 , R 2 , R 3 , n and p are the same as defined above, can be converted to the intermediate of formula (88), for example with chlorosulphonic acid.
  • the final compounds of formula (1) can be prepared by reacting the intermediate of the formula (88) with an appropriate amine of the formula ArNHR 4 , for example, using standard basic conditions such as those known in the literature (e.g., in the presence of sodium hydride in DMF or diisopropylethyamine in THF and the like).
  • the intermediate of formula (87) wherein T, U, V, W, R 1 , R 2 , R 3 , n and p are the same as defined above can be converted to the intermediate of formula (89) by treatment with a nitrating mixture such as for example HNO 3 /H 2 SO 4 .
  • the intermediate of formula (89) can then be reduced with a suitable reducing agent (such as H 2 / Pd/C or Raney-Ni/ NH 2 NH 2 ) to provide the intermediate of formula (90).
  • the final compounds of formula (1) can be prepared by reacting the intermediate of the formula (90) with an appropriate intermediate of the formula ArSO 2 Cl or ArCOCl for example, using standard basic conditions such as those known in the literature (e.g., in the presence of sodium hydride in DMF or diisopropylethyamine in THF and the like).
  • the desired compounds of formula (1) obtained by any of the aforementioned schemes can then be converted into their salts and/or the N-oxides and, if desired, salts of the compounds of the formula (1) obtained are then converted into the free compounds.
  • the N-oxidation may be carried out by any manner known in the art, e.g with the aid of m-chloroperoxybenzoic acid in dichloromethane at room temperature.
  • the substances according to the invention may be isolated and purified by any method known in the art, e.g., by distilling off the solvent in vacuum and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as column chromatography on a suitable support material.
  • Salts can be obtained by dissolving the free compound in a suitable solvent, e.g., in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (e.g., ethanol, isopropanol) which contains the desired acid or base, or to which the desired acid or base is then added.
  • a suitable solvent e.g., in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (e.g., ethanol, isopropanol) which contains the desired acid or base, or to which the desired acid or base is then added.
  • the salts can be obtained by filtering, reprecipitating, precipitating with a non-solvent for the addition salt or by evaporating the solvent. Salts obtained can be converted by basification or acidification into the free compounds which, in turn can be converted into salts.
  • the chlorinated solvent which may be employed may be selected from dichloromethane, 1,2-dichloroethane, chloroform, carbontetrachloride and the like.
  • the aromatic solvents which may be employed may be selected from benzene and toluene.
  • the alchoholic solvents which may be employed may be selected from methanol, ethanol, n-propanol, iso propanol, tert-butanol and the like.
  • the compounds prepared in the above described processes can be obtained in pure form by using known techniques such as crystallization using solvents such as pentane, diethyl ether, isopropyl ether, chloroform, dichloromethane, ethyl acetate, acetone, methanol, ethanol, isopropanol, water or their combinations, or column chromatography using alumina or silica gel and eluting the column with solvents such as hexane, petroleum ether (pet.ether), chloroform, ethyl acetate, acetone, methanol or their combinations.
  • solvents such as pentane, diethyl ether, isopropyl ether, chloroform, dichloromethane, ethyl acetate, acetone, methanol, ethanol, isopropanol, water or their combinations
  • column chromatography using alumina or silica gel and eluting the column with solvents such as hexane,
  • polymorphs of a compound of formula (1) forming part of this invention may be prepared by crystallization of compound of formula (1) under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures, various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or other techniques.
  • the present invention also provides pharmaceutical compositions containing one or more compounds of formula (1) (including derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, enantiomers, and diasteromers) and pharmaceutically acceptable salts thereof (and pharmaceutically acceptable solvates) in combination with a pharmaceutically acceptable excipient, such as a pharmaceutically acceptable carrier or diluent.
  • a pharmaceutically acceptable excipient such as a pharmaceutically acceptable carrier or diluent.
  • the pharmaceutical compositions may be in the form of dosage unit forms, such as tablets, capsules, powders, syrups, solutions, and suspensions and the like.
  • the pharmaceutical compositions may contain suitable solid or liquid carriers or diluents, or be in suitable sterile media to form injectable solutions or suspensions.
  • the compounds of formula (1) can be combined with a suitable solid, liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions or the like.
  • the pharmaceutical compositions may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like.
  • the compounds of the formula (1) can be combined with sterile aqueous or organic media to form injectable solutions or suspensions.
  • injectable solutions or suspensions for example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used as well as aqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or salts with a base of the compounds of formula (1).
  • the injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly.
  • the compounds can also be administered by inhalation when application within the respiratory tract is intended.
  • the compound of Formula (1) can be delivered by respiratory inhalation in the form of an aerosol under pressure. It is preferred to micronize the compound of Formula (1) after it has been homogenised, e.g., in lactose, glucose, higher fatty acids, sodium salt of dioctylsulfosuccinic acid or, most preferably, in carboxymethyl cellulose, in order to achieve a microparticle size of 5 ⁇ m or less for the majority of particles.
  • the aerosol can be mixed with a gas or a liquid propellant for dispensing the active substance.
  • An inhaler or atomizer or nebulizer may be used. Such devices are known.
  • the compound of the structure (1) for inhalation is preferably formulated in the form of a dry powder with micronized particles.
  • the compounds of the invention may also be used in a metered dose inhaler using methods disclosed in U.S. Patent 6, 131,566, incorporated herein by reference in their entirety.
  • the pharmaceutical compositions of the present invention may also contain or be co-administered with one or more known therapeutic agents.
  • compositions according to this invention can be used for the treatment of allergic disorders.
  • the compounds of formula (1) down regulate or inhibit the production of TNF- ⁇ as they are PDE4 inhibitors and therefore are useful in the treatment of variety of allergic and inflammatory diseases including asthma, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjuctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, septic shock, diabetes, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock and adult respiratory distress syndrome.
  • the compounds of the present invention are particularly useful for the treatment of asthma and chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • Yet another embodiment of the invention is a method of treating an inflammatory disease, disorder or condition characterized by or associated with an undesirable inflammatory immune response, or a disease or condition induced by or associated with an excessive secretion of TNF- ⁇ and PDE-4 in a subject in need thereof by administering to the subject a therapeutically effective amount of a PDE-4 inhibitor or a pharmaceutical composition of the present invention.
  • Yet another embodiment of the invention is a method of treating an inflammatory condition or an immune disorder in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound according to formula (1) or a pharmaceutical composition of the present invention.
  • Inflammatory conditions and immune disorders which can be treated with the PDE-4 inhibitors of the present invention include, but are not limited to, asthma, bronchial asthma, chronic obstructive pulmonary disease, allergic rhinitis, eosinophilic granuloma, nephritis, rheumatoid arthritis, cystic fibrosis, chronic bronchitis, multiple sclerosis, Crohn's disease, psoraisis, uticaria, adult vernal cojunctivitis, respiratory distress syndrome, rhematoid spondylitis, osteoarthritis, gouty arthritis, uvelitis, allergic conjunctivitis, inflammatory bowel conditions, ulcerative coalitis, eczema,
  • inflammatory conditions and immune disorders chosen from inflammatory conditions and immune disorders of the lungs, joints, eyes, bowels, skin or heart.
  • inflammatory conditions chosen from asthma and chronic obstructive pulmonary disease.
  • Yet another embodiment of the invention is a method for abating inflammation in an affected organ or tissue by delivering to the organ or tissue a therapeutically effective amount of a PDE-4 inhibitor or a pharmaceutical composition of the present invention.
  • Yet another embodiment of the invention is a method of treating a disease of the central nervous system in a subject in need thereof by administering to the subject a therapeutically effective amount of a PDE-4 inhibitor or a pharmaceutical composition of the present invention.
  • Diseases of the central nervous system tratable with the compounds of the present invention include, but are not limited to, depression, amnesia, dementia, Alzheimers disease, cardiac failure, shock and cerebrovascular disease.
  • Yet another embodiment of the invention is a method of treating insulin resistant diabetes in a subject in need thereof by administering to the subject a therapeutically effective amount of a PDE-4 inhibitor or a pharmaceutical composition of the present invention.
  • Step 2 ethyl 7-methoxy-3-methylbenzo[b]furan-2-carboxylate.
  • Step 3 ethyl 4-formyI-7-methoxy-3-methylbenzo[b]furan-2-carboxylate The solution of ethyl 7-methoxy-3-methylbenzo[b]furan-2-carboxylate (5.Og,
  • Step 5 2-ethyl-4-methyI-7-raethoxy-3-methylbenzo[b]furan-2,4- dicarboxylate.
  • reaction mixture (4.06g, 32.3mmol was added dropwise to the reaction mixture at 80-90 0 C. Reaction mixture was cooled to room temp. Water (300 ml) was added to reaction mixture and acidified with dilute HCl. The precipitate obtained was filtered and dried in oven.
  • reaction mixture 8.6 mmol was added to the reaction mixture at once at the same temp. Reaction mixture was cooled to room temp, and water (200 ml) was added to reaction mixture.
  • Step 8 methyl(6-methoxy-4-oxo-3,4-dihydrobenzo[4,5]furo[2,3-d]pyridazine)-9- carboxylate
  • 2-ethyl 4-methyl 3-formyl-7-methylbenzo[b]furan-2,4- dicarboxylate (185mg, 3.7mmol) was added at room temp.
  • the reaction mixture was stirred at room temp, for 3-4 hrs.
  • Water (100 ml) was added to reaction mixture and the solid obtained was filtered and suck dried. The solid was dried in oven.
  • White colored solid (397mg) was obtained.
  • Step 9 methyl (4-chloro-6-methoxybenzo[4,5]furo[2,3-d]pyridazine)-9- carboxylate
  • Step 10 methyl (6-methoxybenzo[4,5]furo[2,3-d]pyridazine)-9-carboxylate
  • Step 12 4-nitrophenyl 6-methoxybenzo[4,5]furo[2,3-d]pyridazine-9-carboxylate:
  • Step 1 ethyl 2-(2-formyl-6-methoxyphenoxy)acetate
  • Step 2a ethyl 2-(2-cyano-6-methoxyphenoxy)acetate
  • 6-methoxyphenoxy)acetate (8.4Og, 35.5mmol) in ethanol (50ml) was added at room temperature under stirring. Water (100 ml) was added to reaction mixture, acidified with dilute HCl and ethanol was distilled off under vacuum. The solid obtained was filtered and suck dried. Pale yellow coloured solid (7.8g) was obtained m.p. 79-81 0 C.
  • Step 4 4-chloro-6-methoxybenzo[4,5]furo[3,2-d]pyrimidine A suspension of 6-methoxy-3,4-dihydrobenzo[4,5]furo[3,2-d]pyrimidine-4-one
  • reaction mixture was cooled to 0-10 0 C.
  • Water (100 ml) was added dropwise to the reaction mixture at 0-10 0 C.
  • the precipitate obtained was filtered and dried in oven. Yellow colored solid (3.25g) was obtained. m.p. 174.5-176 0 C.
  • Reaction mixture was filtered through cellite bed. Bed was washed with methanol
  • Step 7 6-methoxybenzo[4,5]furo[3,2-d]pyrimidin-9-yI cyanide
  • Step 9 4-nitrophenyl 6-methoxybenzo[4,5]furo[3,2-d]pyrimidine-9-carboxylate A mixture of 6-methoxybenzo[4,5]furo[3,2-d]pyrimidine-9-carboxylic acid (lOOmg,
  • Step 1 l-methoxy-2-(2-propenyloxy) benzene
  • Step 4 7-methoxy-2-methylbenzo[b]furan-4-carboxylic acid
  • acetone 40.0 mL
  • a solution of sulphamic acid 2.4 g, 25.26 mmol
  • sodium chlorite 2.8 g, 31.57 mmol
  • Ice cold water 250 mL was added to reaction mixture and the product separated was filtered and dried at 60- 7O 0 C to give intermediate-4 (3.2 g) as white solid, m.p. 228-233 0 C.
  • Step 5 Methyl-7-methoxy-2-methylbenzo[b]furan-4-carboxylate To a well stirred suspension of 7-methoxy-2-methylbenzo[b]furan-4-carboxylic acid (from step 4) (4.5 g, 24.21 mmol)and powdered potassium carbonate (7.5g, 54.61 mmol) in acetone (740.0 mL) was added dimethyl sulfate (4.1 g, 32.76 mmol) and refluxed for 2-3 hours. Reaction mixture was cooled to room temperature and water (500 mL) was added to it. The organic material separated was extracted with ethyl acetate (3x100ml).
  • Methyl-7-methoxy-2-methylbenzo[b]furan-4-carboxylate (from step 5) (4.0 g, 18.16 mmol) and refluxed for 2-3 hours. Reaction mixture was cooled to room temperature and filtered thorough Celite bed. The filtrate was concentrated under vacuo to give product (3.1 g) as brown oil. The product obtained was taken ahead for next step without further purification.
  • step 6 To a well stirred solution of Methyl-2-bromomethyl-7-methoxybenzo[b]furan-4- carboxylate (step 6) (3.1 g, 10.36 mmol) in dimethyl sulfoxide (30.0 mL) was added powdered sodium carbonate (1.64 g, 15.55 mmol) at 90-95oC and stirred for 2-3 hours. Reaction mixture was cooled to room temperature and diluted with water (300 mL) and extracted with ethyl acetate (3x100 mL). The combined organic layers were washed with water (2x50mL) and dried over anhydrous sodium sulfate. Removal of solvent gave crude product (2.9 g) as brown viscous oil. Purification by silica gel column using chloroform: ethyl acetate (95:5) as an eluent afforded 2.2 g of pure product. m.p. 139-142 0 C.
  • Step 8 (Z)-3-(7-methoxy-4-methyloxycarbonylbenzo[b]furan-2-yl)-2-propenoic acid.
  • Step 9 Methyl-2-[(Z)-2-azidocarbonyl)-l-ethenyl]-7-methoxybenzo[b]furan-4- car boxy late
  • Step 10 Methy 1-1 -hydroxy-6-Methoxy benzof 4,5] fu ro [3,2-c] py ridine-9- carboxylate
  • Step 14 4-Nitrophenyl-6-methoxybenzo[4,5]furo[3,2-c]pyridine-9-carboxylate
  • 6-Methoxybenzo[4,5]furo[3,2-c]pyridine-9-carboxylic acid from step 13) (65 mg, 0.178 mmol), p-nitrophenol (37 mg, 0.267), EDCI (51 mg, 0.267mmol), 4, 4-dimethyl amino pyridine (2.0 mg, 0.017mmol) in DMF (3.0 mL) was heated to 70-75 0 C for 4-5 hours.
  • the residue obtained after removal of solvent under vacuo was triturated with water (5.0 mL) to give intermediate- 15 (55 mg) as yellow solid, m.p. > 25O 0 C.
  • Step 2 2, 4-Diethyl-7-hydroxy-3-methylbenzo[b]furan-2,4-dicarboxylate
  • 2-ethoxycarbonyl-7-hydroxy-3-methylbenzo[b]furan-4-carboxylic acid from step 1) (13 g)
  • COnCH 2 SO 4 in ethanol
  • TLC time-dimethyl-1-butane
  • reaction mixture was concentrated under vacuum.
  • water 500 ml was added to reaction mixture and the precipitate obtained was filtered and dried in oven.
  • the crude solid was purified by silica gel column chromatography using 20% ethyl acetate in chloroform as eluent. 6.5 g buff colored solid was obtained, m.p. - 195-197 0 C.
  • Step 6 Ethyl 6-difIuoromethoxy-4-oxo-3,4-dihydrobcnzo[4,5]furo[2,3- ⁇ flpyridazine-9-carboxylate
  • This compound was synthesized from diethyl 7-difluoromethoxy-3- formyllbenzo[b]furan-2,4-dicarbox ylate as per the procedure described in step 8 of example 1. m.p.- 210-214°C.
  • Step 7 Ethyl 4-chloro-6-difluoromethoxybenzo[4,5]furo[2,3- ⁇ /]pyridazine-9- carboxylate
  • Step 8 Ethyl 6-difl ⁇ ioromethoxybenzo[4,5]furo[2,3- ⁇ /]pyridazine-9-carboxylate
  • Step 9 6-Difluoromethoxybenzo[4,5]furo[2,3- ⁇ /]pyridazine-9-carboxylic acid.
  • This compound was synthesized from ethyl 6-difluoromethoxybenzo[4,5]furo[2,3- */]pyridazine-9-carboxylate by the procedure described in step 11 of example 1. m.p.- above 27O 0 C.
  • Step 10 4-nitrophenyl 6-difluoromethoxybenzo [4,5]furo[2,3-d]pyridazine-9- carboxylate
  • Step 11 N9-(3,5-dichloro-4-pyridyl)-6-difluoromethoxybenzo[4,5]furo[2,3- d] py ridazine-9-carboxamide
  • Step 1 ethyl 4-(2-methoxyphenylsuIfanyI)-3-oxobutanoate
  • Step 2 ethyl 2-(7-methoxybenzene[ ⁇ ]thiophen-3-yl)acetate
  • Ethyl 4-(2-methoxyphenylsulfanyl)-3-oxobutanoate (from step 1) (5 g, 1.86 mmol) was added to the polyphosphoric acid at 80-90 0 C under stirring. Progress of reaction was monitored by TLC. After completion of the reaction, reaction mixture was cooled to room temp and ice (250 g) was added to the reaction mass. The organic mass was extracted by dichloromethane (3 x 100 ml). The combined organic phases were washed with water (3 x 100 ml) followed by brine (100 ml) and dried over anhydrous sodium sulfate. After concentrating organic volume purified on a silica column in pet ether: ethyl acetate (3 %) to get pure product as of yellow solid (2.Og).
  • Ethyl 2-(7-methoxybenzene[Z>]thiophen-3-yl)acetate (from step 2) (2.0 g, 8.0 mmol) was dissolved in Methanol (10 ml) and to the solution added Ethylene glycol saturated with ammonia (10 ml) stirred at room temperature for 48.0 hours. Methanol was evaporated under vacuum Water (50 ml) was added to the reaction mixture and extracted with ethyl acetate (3 x 25 ml).
  • Step 6 Ethyl 8-methoxy-l,2,3,4-tetrahydrobenzo[4,5]thieno[2,3-c]pyridine-2- car boxy late
  • Step 7 Ethyl 5-formyl-8-methoxy-l,2,3,4-tetrahydrobenzo[4,5]thieno[2,3- c]pyridine-2-carboxylate
  • stannic chloride (0.122 ml, 1.05 mmol
  • dichloromethyl methylether (0.07 ml, 0.07 mmol
  • Step 7 2-ethoxycarbonyl-8-methoxy-l,2,3,4-tetrahydrobenzo[4,5]thieno[2,3-c] pyridine-5-carboxylic acid
  • Step 8 2-ethyl-5-(4-nitrophenyl)-8-methoxy-l,2,3,4- tetrahydrobenzo[4,5]thieno[2,3-c] pyridine-2,5-dicarboxylate
  • Step 9 2-ethyl-5-(4-nitrophenyl)-8-methoxy-l v 2,3,4- tetrahydrobenzo[4,5]thieno[2,3-c] pyridine-2,5-dicarboxylate
  • Step 1 2-tert-butyloxycarbonyl-8-methoxy-l, 2,3,4- tetrahydrobenzo[4,5]thieno[2,3-c] pyridine-5-carboxylic acid
  • Step 2 2-(tert-butyl)-5-(4-nitrophenyl)-8-methoxy-l,2,3,4-tetrahydrobenzo[4,5] thieno [2,3-c] pyridine-2,5-dicarboxylate
  • Step 3 tert-butyl 5-(3,5-dichloro-4-pyridylcarbamoyl)-8-methoxy-l, 2,3,4- tetrahydrobenzo[4,5]thieno[2,3-c] pyridine-2-carboxyIate
  • Step 5 2-(7-methoxy-l-benzofuran-2-yI)ethanamine (7-methoxy-l-benzofuran-2-yl)acetonitrile (from step 4) (500 mg, 2.67 mmol) was dissolved in methanol (20 ml). To this cone. HCl (0.038 g, 1.068 mmol) and 10% Pd/C (250 mg) was added and kept for hydrogenation at 40psi for 6h. Reaction mixture was filtered through celite and dried over sodium sulfate and concentrated to yield 500 mg of the product as brown thick liquid.
  • Step 6 Ethyl 2-(7-methoxy-l-benzofuran-2-yl)ethylcarbamate 2-(7-methoxy-l-benzofuran-2-yl)ethanamine (from step 5) (100 mg, 0.523 mmol) was dissolved in THF (4 ml). To this solution triethylamine (0.21 1 g, 2.09 mmol) and ethyl chloroformate (0.085 g, 0.784 mmol) was added at 0 0 C and then stirred at room temperature for 5h. THF was evaporated and the residue was purified by column chromatography using 100-200 mesh silica gel and eluted in 5% ethyl acetate- petroleum ether to obtain 30mg of yellow thick liquid.
  • Step7 2-ethyoxycarbonyl-6-methoxy-l,2,3,4-tetrahydro[l]benzofuro[3,2- c] pyridine: ethyl 2-(7-methoxy-l-benzofuran-2-yl)ethylcarbamate (from step 6) (50 mg, 0.190 mmol) was dissolved in toluene (5 ml). To this para formaldehyde (17mg, 0.570 mmol) and p-toluene sulfonic acid (2.5 mg) was added and subjected to azeotropic distillation for 2h.
  • Step 8 2-ethoxycarbonyl-6-methoxy-l,2,3,4-tetrahydro[l]benzofuro[3,2- c)pyridine-9-carbaldehyde: 2-ethyoxycarbonyl-6-methoxy-l,2,3,4-tetrahydro[l]benzofuro[3,2-c]pyridine (from step 7) (0.420 g, 1.52 mmol) was dissolved in dichloromethane (25 ml).
  • Step 9 2-ethoxycarbonyl-6-methoxy-l,2,3,4-tetrahydro[l]benzofuro[3,2- c]pyridine-9-carboxylic acid
  • Step 10 4-nitrophenyl (2-ethoxycarbonyl-6-methoxy-l,2,3,4-tetrahydro[l]benzo furo[3,2-c]pyridine)-9-carboxylate
  • Step 11 Ethyl 9-(3,5-dichloro-4-pyidylcarbamoyl)-8-methoxy-l,2,3,4-tetrahydro benzo[4,5]furo[3,2-c]pyridine-2-carboxylate
  • Step 2 2-tert-butyl 9-methyl 6-methoxy-l,3,4,5-tetrahydro-2H-pyrido[4,3-A] indole-2, 9-dicarboxylate
  • Step 3 2-t ⁇ rf-butyl 9-methyl -6-methoxy-5-methyl-l,3,4,5-tetrahydro-2H-pyrido [4, 3-b] indole-2, 9-dicarboxylate
  • Step 5 2-terf-butyl 9-(4-nitrophenyl) 6-methoxy-5-methyl-l,3,4,5-tetrahydro-2H- pyrido [4, 3-b] indole-9-dicarboxylate
  • Step 6 tert-butyl 9-(3,5-dichloro-4-pyridinylcarbamoyl)-6-methoxy-5-methyl- l,3,4,5-tetrahydro-lH-pyrido[4,3- ⁇ ]indole-2-carboxylate
  • This compound was synthesised by following the process described from step 3 to step 6 for example 10 except for using benzyl bromide instead of iodomethane in step
  • This compound was synthesised by following the process described from step 3 to step 6 for example 10 except for using cyclopropylmethylbromide instead of iodomethane in step 3.
  • This compound was synthesized from 2-tert-buty ⁇ 9-(4-nitrophenyl) 6-methoxy-5- methyl-l,3,4,5-tetrahydro-2H-pyrido [4, 3-b] indole-9-dicarboxylate (from step 5 of example 10) using the process described in step 6 of example 10. 4-amino-3,5- dichloropyridine was replaced by 4-aminopyridine.
  • Step 1 (7-methoxy-l-benzofuran-3-yl) acetonitrile : The solution of 7-methoxy-l ⁇ - benzofuran-3(2H)-one (reference) (7.5 g, 0.046 mol), cyanoacetic acid (19.55 g, 0.23 mol) and ammonium acetate (7.08 g, 0.092 mol) in xylene was refluxed for 16-18 h. using dean stark apparatus. Xylene was removed under diminished pressure. Brown black residue was taken in ethyl acetate, washed with water and concentrated. On purification on silica gel it yielded (7-methoxy-l-benzofuran-3-yl) acetonitrile (30%).
  • Step 4 Ethyl 8-methoxy-3, 4-dihydro[l]benzof ⁇ iro[2,3-c]pyridine-2(lH)- carboxylate
  • Step 6 Ethyl 5-formyl-8-methoxy-3,4-dihydro[l]benzofuro[2,3-c]pyridine-2(lH)- carboxylate
  • Step 7 2-(ethoxycarbonyl)-8-methoxy-l,2,3,4-tetrahydro[l]benzofuro[2,3- c]pyridine-5-carboxylic acid
  • Step 8 4-nitrophenyl 2-(ethoxycarbonyl)-8-methoxy-l,2,3,4-tetrahydro[l]benzo furo[2,3-c]pyridine-5-carboxylate
  • Step 9 jV-(3,5-dichloropyridin-4-yl)-2-(ethoxycarbonyl)-8-methoxy-l,2,3,4-tetra hydro[l]benzofuro ⁇ jS-cJpyridine-S-carboxamide
  • Step 1 2-(ferf-butoxycarbonyl)-8-methoxy-l,2,3,4-tetrahydro[l]benzofuro[2,3- c]pyridine-5-carboxylic acid 2-(ethoxycarbonyl)-8-methoxy-l,2,3,4-tetrahydro[l]benzofuro[2,3-c]pyridine-5- carboxy- lie acid (1.99 gm, 0.0063 mol) (from Step No.7 of example 19) was taken in
  • Step 2 4-nitrophenyl 2-(tert-butyloxycarbonyl)-8-methoxy-l,2,3,4- tetrahydro[l]benzofuro[2,3-c]pyridine-5-carboxyIate
  • This compound was synthesized from 2-(/er/-butoxycarbonyl)-8-methoxy-l, 2,3,4- tetrahydro[l]benzofuro[2,3-c]pyridine-5-carboxylic acid (from step 1) using the process described in step 8 of example 19.
  • Step 3 ⁇ r -(3,5-dichloropyridin-4-yl)-2-(tert-butyloxycarbonyl)-8-methoxy-l,2,3,4- tetrahydro[l]benzofuro [2,3-c]pyridine-5-carboxamide
  • Step 4 iV-(3,5-dichloropyridin-4-yl)-8-iiiethoxy-l,2,3,4- tetrahydro[l]benzofuro[2,3-c]pyridine-5-carboxamide hydrochloride
  • N-(3,5-dichloropyridin-4-yl)-2-(tert-butoxycarbonyl)-8-methoxy-l,2,3,4- tetrahydro[l]benzofuro [2,3-c]pyridine-5-carboxamide (from step 3) (645 mg, 0.0013mol) was taken in dry ethyl acetate and ethyl acetate saturated with HCl was added to it at 0 0 C. it was then stirred for an hour. Ethyl acetate was removed under diminished pressure and dry solvent ether was added to it.
  • Step 2 2-(t ⁇ rf-butoxycarbonyl)-6-methoxy-l,2,3,4-tetrahydro[l]benzofuro [3,2- c]pyridine-9-carboxylic acid
  • ⁇ -nmr (DMSO-c/ 6 ): ⁇ 1.42(s, 9H), 2.81(br s, 2H), 3.7(t, 2H), 3.95(s, 3H), 4.74(br, s,
  • Step 3 4-nitrophenyl 2-(t ⁇ rf-butyloxycarbonyl)-6-methoxy-l,2,3,4- tetrahydro[l]benzofuro[3,2-c]pyridine-9-carboxylate
  • This compound was synthesized from 2-(tert-butoxycarbonyl)-6-methoxy-l, 2,3,4- tetrahydrofljbenzofuro ⁇ -clpyridine ⁇ -carboxylic acid (from step 2) using the process described in step 8 of example 19.
  • Step 4 N-(3,5-dichloropyridin-4-yl)-2-(te ⁇ butyloxycarbonyl)-6-methoxy-l,2,3,4- tetrahydro[l]benzofuro [3,2-c]pyridine-9-carboxamide
  • This compound was synthesized from 4-nitrophenyl 2-(tert-butyloxycarbonyl)-6- methoxy-l,2,3,4-tetrahydro[l]benzofuro[3,2-c]pyridine-9-carboxylate (from step 3) using the process described in step 9 of example 19.
  • Step 5 N-(3,5-dichloropyridin-4-yl)-6-methoxy-l,2,3,4- tetrahydro[l]benzofuro[3,2-c]pyridine-9-carboxamide hydrochloride
  • ⁇ -nmr (DMSO- ⁇ 5 ) ⁇ : 3.11(br s, 2H), 3.5(br s, 2H), 4.03(s, 3H), 4.29(br s, 2H),
  • Step 2 Methyl 8-methoxy-l-oxo-l,2,3,4-tetrahydro-/?-carboliiie-5-carboxylate
  • Step 3 Methyl 8-methoxy-9-methyl-l-oxo-l,2,3,4-tetrahydro- ⁇ -carboIine-5- carboxylate
  • Step 4 Methyl 8-methoxy-2,9-dimethyl-l-oxo-l,2,3,4-tetrahydro-/?-carboline-5- car boxy late
  • Step 5 8-methoxy-2,9-dimethyl-l-oxo-l,2,3,4-tetrahydro-/?-carboline-5- carboxylic acid
  • Step 6 p-nitrophenyl 8-methoxy-2,9-dimethyl-l-oxo-l,2,3,4-tetrahydro-/?- carboline-5-carboxylate
  • Step 7 ⁇ 43,5-dichloropyridin-4-yl)-2,9-dimethyl-8-methoxy-l-oxo-l,2,3,4- tetrahydro-/J-carboline-5-carboxaniide
  • Step 1 l-methoxy-2-(2-propenyloxy) benzene
  • Step 2 7-methoxy-2-methylbenzo[b]furan
  • l-methoxy-2-(2-propenyloxy) benzene (1 18.0 g, 0.728 moles) in N,N-diethyl aniline (1.0 L)
  • cesium fluoride 134 g, 0.874 mmoles
  • Reaction mixture was cooled to room temperature and 10% aqueous HCl solution (3.0 lit) was added followed by addition of ethyl acetate (2.0L).
  • the mixture was the filtered through Celite bed.
  • HMPA HMPA (62.0 g) was added slowly and reaction mixture was stirred at the same temperature for 4-5 hr. reaction mixture was then bring to 50-60 0 C, water (500 mL) was added and layers were separated. The aqueous layer was acidified (pH 4-5). The solid separated was filtered, washed with water (3x200 mL) and dried to get light yellow solid product (44.0 g).
  • Step 8 Methyl-T-cyclopentyloxy-l-bromomethylbenzofbJfuran ⁇ -carboxylate
  • Step 10 (Z)-3-(7-cyclopentyloxy-4-raethyloxycarbonyIbenzo[b]furan-2-yl)-2- propenoic acid.
  • Step 11 Methyl-2-[(Z)-2-azidocarbonyl)-l-ethenyl]-7-methoxybenzo[b]furan-4- carboxylate
  • Step 12 Methyl-l-hydroxy-6-cyclopentyloxybenzo[4,5]furo[3,2-c]pyridine-9- carboxylate
  • Step 15 Methyl -6-difluoromethyloxybenzo[4,5]furo[3,2-c]pyridine-9- carboxylate
  • Step 16 6-DifluoromethyIoxybenzo[4,5]furo[3,2-c]pyridine-9-carboxylic acid
  • Methyl -6-difluoromethyloxybenzo[4,5]furo[3,2-c]pyridine-9- carboxylate 6.5 g, 0.0221 moles
  • sodium hydroxide 4.Og, 0.110 moles
  • Step 17 4-Nitrophenyl 6-difluoromethyIoxybenzo[4,5]furo[3,2-c]pyridine-9- carboxylate
  • Step 18 N9-(3,5-dichloro-4-pyridyl)-6-difluoromethoxybenzo[4,5]furo[3,2-c] pyridine-9-carboxamide
  • Step 1 4-amino-3,5-dichloro pyridine-N-oxide :To a solution of 4-amino-3,5- dichloro pyridine (5.0gm, 0.0306 moles) in chloroform (100 mL) was added 20% peracetic acid solution (200 ml, 0.597 moles) (20% peracetic acid was prepared as per Vogel's Practical Organic Chemistry, Vol. V, page no. 458). Reaction mixture was then stirred at room temperature for 48 hrs, cooled to 5-lOoC and quenched with sodium sulphite till iodide test disappeared. Chloroform as well as acetic acid was removed under reduced pressure. The residue obtained was purified on silica gel column using 5% methanol in chloroform as an eluent to give product as light yellow solid.
  • Step 2 3,5-dichloro-4-(6-difluoromethoxybenzo[4,5]furo[2,3-tf]pyridazine-9- ylcarboxamido)-l-pyridiniumolate : To a well stirred suspension of 4-nitrophenyl 6-difluoromethoxybenzo [4,5] furo [2,3-d]pyridazine-9-carboxylate (100 mg, 0.2481 mmoles), 4-amino-3,5-dichloro pyridine-N-oxide (39 mg, 0.2233 mmoles) in DMF (5.0 mL) was added NaH(60%) (4 x 5 mg, 0.4962 mmoles) at 5-1O 0 C.
  • reaction mixture was then allowed to come to room temperature in 2.0 hrs. Reaction mixture was then diluted with water (25mL) and acidified with acetic acid. The slid separated was extracted with ethyl acetate (3x1 OmL). The combined organic layers were washed with water and dried over anhy. sodium sulfate. The residue obtained after removal of solvent was purified on silica gel column using 8%methanol in chloroform as an eluent to give product as off-white solid. Yield: 40mg m.p. > 25O 0 C
  • Step I ethyl 6-difluoromethoxy-3-ethyl-4-oxo-3,4-dihydrobenzo[4,5]furo[2,3- d]pyridazine-9-carboxylate
  • Step II 6-difluoromethoxy-3-ethyI-4-oxo-3,4-dihydrobenzo[4,5]furo[2,3- d]pyridazine-9-carboxylic acid.

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Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008069963A1 (en) * 2006-12-01 2008-06-12 Medivation Neurology, Inc. Means for improving cognitive functions and memory based on hydrogenated pyrido (4,3-b) indoles (variants), pharmacological means based thereon and method for the use thereof
WO2008081282A2 (en) * 2006-12-20 2008-07-10 Glenmark Pharmaceuticals S.A. Process for the synthesis of n9-(3,5-dichloro-4-pyridyl)-6- difluoromethoxybenzo(4,5)furo(3,2-c)pyridine-9-carboxamide and salts thereof
WO2008093221A2 (en) * 2007-02-01 2008-08-07 Glenmark Pharmaceuticals, S.A. Pharmaceutical compositions containing pde4 inhibitor for the treatment of inflammatory and allergic disorders
WO2008142542A2 (en) * 2007-05-22 2008-11-27 Glenmark Pharmaceuticals, S.A. Processes for preparing benzofuro [3, 2-c] pyridine- 9-carbaldehyde derivatives as novel intermediates for the synthesis of pde iv inhibitors
WO2009055828A1 (en) * 2007-10-25 2009-04-30 Medivation Technologies, Inc. New tetracyclic compounds
EP2070913A1 (en) 2007-12-14 2009-06-17 CHIESI FARMACEUTICI S.p.A. Ester derivatives as phosphodiesterase inhibitors
JP2010502689A (ja) * 2006-09-11 2010-01-28 マトリックス ラボラトリーズ リミテッド Ｐｄｅ−４およびｐｄｅ−１０の阻害剤としてのジベンゾフラン誘導体
WO2011132051A2 (en) * 2010-04-19 2011-10-27 Glenmark Pharmaceuticals S.A. Tricycle compounds as phosphodiesterase-10 inhibitors
US8119809B2 (en) 2007-11-16 2012-02-21 Rigel Pharmaceuticals, Inc. AMPK-activating heterocycloalkyloxy(hetero)aryl carboxamide, sulfonamide and amine compounds and methods for using the same
US8129390B2 (en) 2007-12-12 2012-03-06 Rigel Pharmaceuticals, Inc. Carboxamide, sulfonamide and amine compounds and methods for using the same
WO2012098495A1 (en) 2011-01-19 2012-07-26 Glenmark Pharmaceuticals Sa Pharmaceutical composition that includes revamilast and a beta-2 agonist
WO2012110946A1 (en) 2011-02-17 2012-08-23 Glenmark Pharmaceuticals Sa Pharmaceutical composition comprising the pde4 enzyme inhibitor revamilast and a disease modifying agent, preferably methotrexate
US8314107B2 (en) 2008-04-23 2012-11-20 Rigel Pharmaceuticals, Inc. Carboxamide compounds and methods for using the same
WO2012168907A1 (en) 2011-06-10 2012-12-13 Glenmark Pharmaceuticals Sa Pharmaceutical composition comprising revamilast and montelukast or zafirlukast
US8349839B2 (en) 2009-04-09 2013-01-08 Boehringer Ingelheim International Gmbh Inhibitors of HIV replication
WO2013084182A1 (en) 2011-12-08 2013-06-13 Glenmark Pharmaceuticals S.A. Pharmaceutical composition that includes a pde4 enzyme inhibitor and an analgesic agent
US8575186B2 (en) 2009-10-05 2013-11-05 Albany Molecular Research, Inc. Epiminocycloalkyl[b] indole derivatives as serotonin sub-type 6 (5-HT6) modulators and uses thereof
US8618299B2 (en) 2009-07-01 2013-12-31 Albany Molecular Research, Inc. Azinone-substituted azapolycycle MCH-1 antagonists, methods of making, and use thereof
US8629158B2 (en) 2009-07-01 2014-01-14 Albany Molecular Research, Inc. Azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof
US8637501B2 (en) 2009-07-01 2014-01-28 Albany Molecular Research, Inc. Azinone-substituted azepino[b]indole and pyrido-pyrrolo-azepine MCH-1 antagonists, methods of making, and use thereof
US8697700B2 (en) 2010-12-21 2014-04-15 Albany Molecular Research, Inc. Piperazinone-substituted tetrahydro-carboline MCH-1 antagonists, methods of making, and uses thereof
US8716308B2 (en) 2008-01-11 2014-05-06 Albany Molecular Research, Inc. (1-azinone)-substituted pyridoindoles
US8741919B2 (en) 2009-04-29 2014-06-03 Medivation Technologies, Inc. Pyrido[4,3-B]indoles and methods of use
US8815843B2 (en) 2011-02-18 2014-08-26 Medivation Technologies, Inc. Compounds and methods of treating diabetes
US8993765B2 (en) 2010-12-21 2015-03-31 Albany Molecular Research, Inc. Tetrahydro-azacarboline MCH-1 antagonists, methods of making, and uses thereof
US9067949B2 (en) 2011-01-19 2015-06-30 Albany Molecular Research, Inc. Benzofuro[3,2-c] pyridines and related analogs as serotonin sub-type 6 (5-HT6) modulators for the treatment of obesity, metabolic syndrome, cognition and schizophrenia
US9073925B2 (en) 2009-07-01 2015-07-07 Albany Molecular Research, Inc. Azinone-substituted azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof
US9255094B2 (en) 2009-04-29 2016-02-09 Medivation Technologies, Inc. Pyrido[4,3-B]indoles and methods of use
US9334290B2 (en) 2013-06-25 2016-05-10 Bristol-Myers Squibb Company Substituted tetrahydrocarbazole and carbazole carboxamide compounds
CN106496322A (zh) * 2015-09-07 2017-03-15 江苏恒瑞医药股份有限公司 人胰岛素或其类似物的酰化衍生物的制备方法
US9688629B2 (en) 2014-10-24 2017-06-27 Bristol-Myers Squibb Company Indole carboxamide compounds
US9714234B2 (en) 2013-06-25 2017-07-25 Bristol-Myers Squibb Company Carbazole carboxamide compounds
CN106983748A (zh) * 2015-12-09 2017-07-28 财团法人食品工业发展研究所 β‑咔啉生物碱在抑制黄嘌呤氧化酶活性中的用途
US10023534B2 (en) 2014-10-24 2018-07-17 Bristol-Myers Squibb Company Carbazole and tetrahydrocarbazole compounds useful as inhibitors of BTK
US10266491B2 (en) 2014-10-24 2019-04-23 Bristol-Myers Squibb Company Carbazole derivatives

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI507410B (zh) * 2010-06-24 2015-11-11 Leo Pharma As 新穎磷酸二酯酶抑制劑
JP6545148B2 (ja) 2013-03-13 2019-07-17 フラットリー ディスカバリー ラブ，エルエルシー ピリダジノン化合物及び嚢胞性線維症の治療のための方法
CN112979667B (zh) * 2019-12-02 2022-04-22 首都医科大学 二氧六环修饰的四氢咔啉-3-甲酰-The,其合成,活性和应用
CN112898376B (zh) * 2019-12-02 2022-06-24 首都医科大学 二氧六环修饰的四氢咔啉-3-甲酰-The-HGK,其制备,抗肿瘤活性和应用

Family Cites Families (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1041861A (en) 1962-03-14 1966-09-07 Organon Labor Ltd Pyrrolidone derivatives and pharmaceutical preparations containing them
NL7008628A (es) 1969-06-25 1970-12-29
US3759948A (en) 1969-06-25 1973-09-18 Merck & Co Inc Non-steroid anti-inflammatory compounds
US3846553A (en) 1969-12-03 1974-11-05 Merck & Co Inc 3-substituted-2-pyridones in the treatment of pain, fever or inflammation
NL7016899A (es) 1969-12-03 1971-06-07
US4222944A (en) 1978-07-31 1980-09-16 Hoffmann-La Roche Inc. Halo-3-dibenzofuran alkanonitriles
JPS62158253A (ja) 1985-12-28 1987-07-14 Kirin Brewery Co Ltd ４−アミノピリジンアミド誘導体
JPH0812430B2 (ja) 1986-07-07 1996-02-07 キヤノン株式会社 電子写真感光体
EP0257956B2 (en) 1986-08-19 2000-11-22 Genentech, Inc. Use of polypeptide growth factors and cytokines for the manufacture of a device and of a dispersion
JPS63250378A (ja) * 1987-04-07 1988-10-18 Mitsubishi Kasei Corp インド−ル誘導体
US5202344A (en) 1990-12-11 1993-04-13 G. D. Searle & Co. N-substituted lactams useful as cholecystokinin antagonists
IE71647B1 (en) 1991-01-28 1997-02-26 Rhone Poulenc Rorer Ltd Benzamide derivatives
US5602173A (en) 1992-04-02 1997-02-11 Smithkline Beecham Corporation Compounds useful for treating allergic and inflammatory diseases
WO1994002465A1 (en) 1992-07-28 1994-02-03 Rhone-Poulenc Rorer Limited INHIBITORS OF c-AMP PHOSPHODIESTERASE AND TNF
MX9306311A (es) 1992-10-13 1994-04-29 Smithkline Beecham Plc Compuestos antagonistas del receptor de 5-ht4, procedimiento para su preparacion y composiciones farmaceuticas que los contienen
US5814651A (en) 1992-12-02 1998-09-29 Pfizer Inc. Catechol diethers as selective PDEIV inhibitors
GB9304920D0 (en) 1993-03-10 1993-04-28 Celltech Ltd Chemical compounds
DK0706513T3 (da) 1993-07-02 2002-09-09 Altana Pharma Ag Fluoralkoxysubstituerede benzamider og anvendelse deraf som cyklisk-nukleotid phosphodiesteraseinhibitorer
GB9315595D0 (en) 1993-07-28 1993-09-08 Res Inst Medicine Chem New compounds
WO1995009837A1 (en) 1993-10-01 1995-04-13 Smithkline Beecham Corporation Cyano compounds
GB9401460D0 (en) 1994-01-26 1994-03-23 Rhone Poulenc Rorer Ltd Compositions of matter
GB9404706D0 (en) 1994-03-11 1994-04-27 Smithkline Beecham Corp Compounds
CZ24197A3 (en) 1994-07-27 1997-08-13 Sankyo Co Heterocyclic compounds, usable as allosteric efectors in muscarine receptors
JPH11509433A (ja) 1995-04-14 1999-08-24 グラクソ、ウェルカム、インコーポレーテッド アルブテロール用計量投与用吸入器
US6514996B2 (en) * 1995-05-19 2003-02-04 Kyowa Hakko Kogyo Co., Ltd. Derivatives of benzofuran or benzodioxole
DE19616573C2 (de) 1996-04-25 1999-03-04 Pari Gmbh Verwendung unterkritischer Treibmittelmischungen und Aerosole für die Mikronisierung von Arzneimitteln mit Hilfe dichter Gase
CA2256716A1 (en) 1996-09-04 1998-03-12 Warner-Lambert Company Matrix metalloproteinase inhibitors and their therapeutic uses
US6177440B1 (en) * 1996-10-30 2001-01-23 Eli Lilly And Company Substituted tricyclics
JP3530004B2 (ja) 1998-02-06 2004-05-24 株式会社日立ユニシアオートモティブ 吸入式投薬器
DE69939689D1 (de) 1998-03-19 2008-11-20 Vertex Pharma Caspase inhibitoren
US6110962A (en) 1998-05-12 2000-08-29 American Home Products Corporation 11-aryl-benzo[B]naphtho[2,3-D]furans and 11-aryl-benzo[B]naphtho[2,3-D]thiophenes useful in the treatment of insulin resistance and hyperglycemia
CN1308627A (zh) 1998-05-12 2001-08-15 美国家用产品公司 可用于治疗胰岛素抗性和高血糖的11－芳基－苯并[b]萘并[2,3－d]呋喃和11－芳基－苯并[b]萘并[2,3－d]噻吩
US6887870B1 (en) 1999-10-12 2005-05-03 Bristol-Myers Squibb Company Heterocyclic sodium/proton exchange inhibitors and method
PL360678A1 (en) 2000-03-17 2004-09-20 Bristol-Myers Squibb Pharma Company Cyclic beta-amino acid derivatives as inhibitors of matrix metalloproteases and tnf-alpha
DE60125026T2 (de) 2000-03-23 2007-06-28 Takeda Pharmaceutical Co. Ltd. Fluorisochinolinderivate, verfahren zu ihrer herstellung und ihre anwendung
WO2002060867A2 (en) 2001-01-29 2002-08-08 Insight Strategy And Marketing Ltd Carbazole derivatives and their uses as heparanase inhibitors
US20020128920A1 (en) 2001-03-06 2002-09-12 Dilip Chopra System and method for providing lowest costs purchasing
WO2002072567A2 (en) 2001-03-13 2002-09-19 Glenmark Pharmaceuticals Limited Heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them
WO2004016596A1 (en) 2002-08-19 2004-02-26 Glenmark Pharmaceuticals Limited Condensed heterocyclic compounds as pde-iv inhibitors for the treatment of inflammatory and allergic disorders
WO2004022536A1 (en) 2002-09-04 2004-03-18 Glenmark Pharmaceuticals Limited New heterocyclic amide compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them
DE60317918T2 (de) 2002-10-23 2009-01-29 Glenmark Pharmaceuticals Ltd. Tricyclische verbindungen zur behandlung von entzündlichen und allergischen erkrankungen verfahren zu deren herstellung und sie enthaltende pharmazeutische zusammensetzungen
WO2004069831A1 (en) 2003-02-10 2004-08-19 Glenmark Pharmaceuticals Ltd. Tricyclic compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation
KR20060017494A (ko) 2003-04-11 2006-02-23 그렌마크 파머수티칼스 에스. 아. 염증 및 알레르기성 질환 치료용으로 유용한 신규 헤테로사이클릭 화합물, 이의 제조방법 및 이를 함유하는 약학 조성물

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BRITISH JOURNAL OF PHARMACOLOGY, vol. 128, 1999, pages 1393 - 1398
NATURE MEDICINE, vol. 1, 1995, pages 211 - 214

Cited By (72)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010502689A (ja) * 2006-09-11 2010-01-28 マトリックス ラボラトリーズ リミテッド Ｐｄｅ−４およびｐｄｅ−１０の阻害剤としてのジベンゾフラン誘導体
WO2008069963A1 (en) * 2006-12-01 2008-06-12 Medivation Neurology, Inc. Means for improving cognitive functions and memory based on hydrogenated pyrido (4,3-b) indoles (variants), pharmacological means based thereon and method for the use thereof
WO2008081282A2 (en) * 2006-12-20 2008-07-10 Glenmark Pharmaceuticals S.A. Process for the synthesis of n9-(3,5-dichloro-4-pyridyl)-6- difluoromethoxybenzo(4,5)furo(3,2-c)pyridine-9-carboxamide and salts thereof
WO2008081282A3 (en) * 2006-12-20 2008-10-23 Glenmark Pharmaceuticals Sa Process for the synthesis of n9-(3,5-dichloro-4-pyridyl)-6- difluoromethoxybenzo(4,5)furo(3,2-c)pyridine-9-carboxamide and salts thereof
WO2008093221A2 (en) * 2007-02-01 2008-08-07 Glenmark Pharmaceuticals, S.A. Pharmaceutical compositions containing pde4 inhibitor for the treatment of inflammatory and allergic disorders
WO2008093221A3 (en) * 2007-02-01 2008-10-16 Glenmark Pharmaceuticals Sa Pharmaceutical compositions containing pde4 inhibitor for the treatment of inflammatory and allergic disorders
WO2008142542A2 (en) * 2007-05-22 2008-11-27 Glenmark Pharmaceuticals, S.A. Processes for preparing benzofuro [3, 2-c] pyridine- 9-carbaldehyde derivatives as novel intermediates for the synthesis of pde iv inhibitors
WO2008142542A3 (en) * 2007-05-22 2009-03-26 Glenmark Pharmaceuticals Sa Processes for preparing benzofuro [3, 2-c] pyridine- 9-carbaldehyde derivatives as novel intermediates for the synthesis of pde iv inhibitors
US8524905B2 (en) 2007-05-22 2013-09-03 Glenmark Pharmaceuticals S.A. Processes for preparing 6-(difluoromethoxy)[1]benzofuro[3,2-c]pyridine-9-carbaldehyde, a novel intermediate for the synthesis of PDE IV inhibitors
US9096591B2 (en) 2007-10-25 2015-08-04 Medivation Technologies, Inc. Tetracyclic compounds
US8999978B2 (en) 2007-10-25 2015-04-07 Medivation Technologies, Inc. Tetracyclic compounds
CN106188043A (zh) * 2007-10-25 2016-12-07 梅迪维新技术公司 四环化合物
US9034880B2 (en) 2007-10-25 2015-05-19 Medivation Technologies, Inc. Tetracyclic compounds
WO2009055828A1 (en) * 2007-10-25 2009-04-30 Medivation Technologies, Inc. New tetracyclic compounds
US8338408B2 (en) 2007-10-25 2012-12-25 Medivation Technologies, Inc. Tetracyclic compounds
US9181240B2 (en) 2007-10-25 2015-11-10 Medivation Technologies, Inc. Tetracyclic compounds
US8119809B2 (en) 2007-11-16 2012-02-21 Rigel Pharmaceuticals, Inc. AMPK-activating heterocycloalkyloxy(hetero)aryl carboxamide, sulfonamide and amine compounds and methods for using the same
US9174964B2 (en) 2007-11-16 2015-11-03 Rigel Pharmaceuticals, Inc. AMPK-activating piperidinyloxy-substituted 2,3-dihydro-1H-indene-1-amine compounds and pharmaceutical compositions including the same
US8569340B2 (en) 2007-11-16 2013-10-29 Rigel Pharmaceuticals, Inc. AMPK-activating piperidinyloxypyiridine carboxamide and sulfonamide compounds and methods for using the same
US8895578B2 (en) 2007-12-12 2014-11-25 Rigel Pharmaceuticals, Inc. Carboxamide, sulfonamide and amine compounds and methods for using the same
US8129390B2 (en) 2007-12-12 2012-03-06 Rigel Pharmaceuticals, Inc. Carboxamide, sulfonamide and amine compounds and methods for using the same
US8557822B2 (en) 2007-12-12 2013-10-15 Rigel Pharmaceuticals, Inc. Carboxamide, sulfonamide and amine compounds and methods for using the same
EP2070913A1 (en) 2007-12-14 2009-06-17 CHIESI FARMACEUTICI S.p.A. Ester derivatives as phosphodiesterase inhibitors
US7968724B2 (en) 2007-12-14 2011-06-28 Chiesi Farmaceutici S.P.A. Ester derivatives as phosphodiesterase inhibitors
US9296743B2 (en) 2008-01-11 2016-03-29 Albany Molecular Research, Inc. (1-azinone)-substituted pyridoindoles
US9650378B2 (en) 2008-01-11 2017-05-16 Albany Molecular Research, Inc. (1-azinone)-substituted pyridoindoles
US8716308B2 (en) 2008-01-11 2014-05-06 Albany Molecular Research, Inc. (1-azinone)-substituted pyridoindoles
US9255085B2 (en) 2008-04-23 2016-02-09 Rigel Pharmaceuticals, Inc. Carboxamide compounds and methods for using the same
US8314107B2 (en) 2008-04-23 2012-11-20 Rigel Pharmaceuticals, Inc. Carboxamide compounds and methods for using the same
US9062052B2 (en) 2008-04-23 2015-06-23 Rigel Pharmaceuticals, Inc. Carboxamide compounds and methods for using the same
US9353111B2 (en) 2008-04-23 2016-05-31 Rigel Pharmaceuticals, Inc. Carboxamide compounds and methods for using the same
US8785449B2 (en) 2008-04-23 2014-07-22 Rigel Pharmaceuticals, Inc. Carboxamide compounds and methods for using the same
US8871770B2 (en) 2008-04-23 2014-10-28 Rigel Pharmaceuticals Inc. Carboxamide compounds and methods for using the same
US8349839B2 (en) 2009-04-09 2013-01-08 Boehringer Ingelheim International Gmbh Inhibitors of HIV replication
US8927571B2 (en) 2009-04-29 2015-01-06 Medivation Technologies, Inc. Pyrido[4,3-B]indoles and methods of use
US8741919B2 (en) 2009-04-29 2014-06-03 Medivation Technologies, Inc. Pyrido[4,3-B]indoles and methods of use
US9255094B2 (en) 2009-04-29 2016-02-09 Medivation Technologies, Inc. Pyrido[4,3-B]indoles and methods of use
US8637501B2 (en) 2009-07-01 2014-01-28 Albany Molecular Research, Inc. Azinone-substituted azepino[b]indole and pyrido-pyrrolo-azepine MCH-1 antagonists, methods of making, and use thereof
US8629158B2 (en) 2009-07-01 2014-01-14 Albany Molecular Research, Inc. Azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof
US9073925B2 (en) 2009-07-01 2015-07-07 Albany Molecular Research, Inc. Azinone-substituted azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof
US8618299B2 (en) 2009-07-01 2013-12-31 Albany Molecular Research, Inc. Azinone-substituted azapolycycle MCH-1 antagonists, methods of making, and use thereof
US8575186B2 (en) 2009-10-05 2013-11-05 Albany Molecular Research, Inc. Epiminocycloalkyl[b] indole derivatives as serotonin sub-type 6 (5-HT6) modulators and uses thereof
WO2011132051A3 (en) * 2010-04-19 2012-01-19 Glenmark Pharmaceuticals S.A. Tricycle compounds as phosphodiesterase-10 inhibitors
WO2011132051A2 (en) * 2010-04-19 2011-10-27 Glenmark Pharmaceuticals S.A. Tricycle compounds as phosphodiesterase-10 inhibitors
US8697700B2 (en) 2010-12-21 2014-04-15 Albany Molecular Research, Inc. Piperazinone-substituted tetrahydro-carboline MCH-1 antagonists, methods of making, and uses thereof
US8993765B2 (en) 2010-12-21 2015-03-31 Albany Molecular Research, Inc. Tetrahydro-azacarboline MCH-1 antagonists, methods of making, and uses thereof
US9067949B2 (en) 2011-01-19 2015-06-30 Albany Molecular Research, Inc. Benzofuro[3,2-c] pyridines and related analogs as serotonin sub-type 6 (5-HT6) modulators for the treatment of obesity, metabolic syndrome, cognition and schizophrenia
WO2012098495A1 (en) 2011-01-19 2012-07-26 Glenmark Pharmaceuticals Sa Pharmaceutical composition that includes revamilast and a beta-2 agonist
WO2012110946A1 (en) 2011-02-17 2012-08-23 Glenmark Pharmaceuticals Sa Pharmaceutical composition comprising the pde4 enzyme inhibitor revamilast and a disease modifying agent, preferably methotrexate
US9550782B2 (en) 2011-02-18 2017-01-24 Medivation Technologies, Inc. Compounds and methods for treating diabetes
US9527854B2 (en) 2011-02-18 2016-12-27 Medivation Technologies, Inc. Compounds and methods for treatment of hypertension
US8815843B2 (en) 2011-02-18 2014-08-26 Medivation Technologies, Inc. Compounds and methods of treating diabetes
WO2012168907A1 (en) 2011-06-10 2012-12-13 Glenmark Pharmaceuticals Sa Pharmaceutical composition comprising revamilast and montelukast or zafirlukast
WO2013084182A1 (en) 2011-12-08 2013-06-13 Glenmark Pharmaceuticals S.A. Pharmaceutical composition that includes a pde4 enzyme inhibitor and an analgesic agent
US9850258B2 (en) 2013-06-25 2017-12-26 Bristol-Myers Squibb Company Substituted tetrahydrocarbazole and carbazole carboxamide compounds
US10435415B2 (en) 2013-06-25 2019-10-08 Bristol-Myers Squibb Company Substituted tetrahydrocarbazole and carbazole carboxamide compounds
US10106559B2 (en) 2013-06-25 2018-10-23 Bristol-Myers Squibb Company Substituted tetrahydrocarbazole and carbazole carboxamide compounds
US9714234B2 (en) 2013-06-25 2017-07-25 Bristol-Myers Squibb Company Carbazole carboxamide compounds
US9334290B2 (en) 2013-06-25 2016-05-10 Bristol-Myers Squibb Company Substituted tetrahydrocarbazole and carbazole carboxamide compounds
US10329274B2 (en) 2014-10-24 2019-06-25 Bristol-Myers Squibb Company Indole carboxamide compounds
US9920031B2 (en) 2014-10-24 2018-03-20 Bristol-Myers Squibb Company Indole carboxamide compounds
US10023534B2 (en) 2014-10-24 2018-07-17 Bristol-Myers Squibb Company Carbazole and tetrahydrocarbazole compounds useful as inhibitors of BTK
US9688629B2 (en) 2014-10-24 2017-06-27 Bristol-Myers Squibb Company Indole carboxamide compounds
US10266491B2 (en) 2014-10-24 2019-04-23 Bristol-Myers Squibb Company Carbazole derivatives
US9802915B2 (en) 2014-10-24 2017-10-31 Bristol-Myers Squibb Company Indole carboxamide compounds
US10604504B2 (en) 2014-10-24 2020-03-31 Bristol-Myers Squibb Company Indole carboxamide compounds
US10676434B2 (en) 2014-10-24 2020-06-09 Bristol-Myers Squibb Company Carbazole derivatives
US11053197B2 (en) 2014-10-24 2021-07-06 Bristol-Myers Squibb Company Carbazole derivatives
US11623921B2 (en) 2014-10-24 2023-04-11 Bristol-Myers Squibb Company Indole carboxamide compounds
CN106496322A (zh) * 2015-09-07 2017-03-15 江苏恒瑞医药股份有限公司 人胰岛素或其类似物的酰化衍生物的制备方法
CN106983748A (zh) * 2015-12-09 2017-07-28 财团法人食品工业发展研究所 β‑咔啉生物碱在抑制黄嘌呤氧化酶活性中的用途
CN106983748B (zh) * 2015-12-09 2019-07-26 财团法人食品工业发展研究所 β-咔啉生物碱在抑制黄嘌呤氧化酶活性中的用途

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